Phenotype of a British North Carolina macular dystrophy family linked to chromosome 6q.

AIMS: To document the phenotype of an autosomal dominant macular dystrophy diagnosed as having North Carolina macular dystrophy (NCMD) in this British family, and to verify that the disease locus corresponds with that of MCDR1 on chromosome 6q. METHODS: 37 family members were examined and the phenotype characterised. DNA samples from the affected members, 19 unaffected and five spouses, were used to perform linkage analysis with six microsatellite marker loci situated within the MCDR1 region of chromosome 6q. RESULTS: Every affected family member had lesions characteristic of NCMD, which developed early in life and usually remain stable thereafter. Although fundus changes are evident in the periphery, all tests revealed that functional loss is restricted to the macula. Some patients with large macular lesions had good visual acuity with fixation at the edge of the lesion at 5 degrees eccentricity. Significant linkage to the MCDR1 locus on chromosome 6q was obtained with three marker loci, with a maximum lod score of 5.9 (q = 0.00) obtained with D6S249. CONCLUSION: This family has the typical phenotype NCMD, and the causative gene was linked to the disease locus (MCDR1) on chromosome 6q. Early onset and localisation of the disease to the central macula allow specialisation of eccentric retina in some eyes with resultant good visual acuity.

Sorsby fundus dystrophy: reevaluation of variable expressivity in patients carrying a TIMP3 founder mutation.

Interfamilial phenotypic variations in Sorsby fundus dystrophy (SFD) have given rise to controversy as to whether SFD constitutes more than 1 nosologic entity. The recent identification of the tissue inhibitor of metalloproteinases-3 (TIMP3) as the gene causing SFD has made it possible to readdress the question of genetic and clinical heterogeneity. In this study, we have extended previous findings on a Ser181Cys founder mutation in SFD families from the British Isles and show that carriers of this mutation residing in Canada, the United States, and South Africa likewise are descendants of the British ancestor. In addition, we have reevaluated the question of variable SFD phenotypes by analyzing the available clinical data on carriers of the Ser181Cys mutation.

Assessment of the phenotypic range seen in Doyne honeycomb retinal dystrophy.

OBJECTIVE: Using molecular genetics as the basis for diagnosis, to assess the phenotype in the family originally described as having dominantly inherited Doyne honeycomb retinal dystrophy (DHRD) linked to chromosome 2p16. DESIGN: Clinical examination including fluorescein angiography was undertaken in 107 family members. Nine affected patients underwent electroretinography, perimetry, dark adaptometry, color-contrast sensitivity measurement, and autofluorescent fundus imaging. PATIENTS: The disease-associated haplotype used to allocate disease status was based on our further refinement of the DHRD locus to between loci D2S2739 and D2S378. The study identified 50 affected patients. In addition, previously published information on a further 8 individuals was used. The study population represented 6 generations of a 9-generation pedigree. RESULTS: Three types of deposits were seen: large, soft drusen at the macula and abutting the optic nerve head; small, hard deposits that in some patients radiated from the macula; and autofluorescent deposits. Most younger affected individuals exhibited small hard drusen only at the macula and had normal visual function. Information on 2 patients suggested that DHRD can be a cause of childhood-onset blindness. Advanced disease was associated with severe visual loss and posterior pole atrophy without signs of drusen. Advanced age was not invariably associated with severe visual loss. CONCLUSIONS: Previously identified characteristics of DHRD were confirmed and new features identified. Contrary to previous reports, the constancy and severity of radial (basal laminar) drusen seen clinically are the only features that can be used to differentiate between DHRD and malattia leventinese. The highly variable phenotype suggests that the influence of the DHRD-mutant gene may be modulated by other genetic and/or environmental factors.

Localisation of a gene for dominant cone-rod dystrophy (CORD6) to chromosome 17p.

We have performed genetic linkage analysis on a four generation British family with cone-rod dystrophy. Significant linkage to the disease gene was obtained with eight marker loci situated on chromosome 17p12-p13. A maximum two-point lod score of 5.93 with no recombination was obtained with marker locus D17S1844. Critical recombinants identified with flanking marker loci placed the disease gene between D17S796/D17S938 and D17S954, an interval estimated to be 8 cM in size. This new localisation for autosomal dominant cone-rod dystrophy (CORD6) overlaps with regions attributed previously to Leber's congenital amaurosis, central areolar choroidal dystrophy and dominant cone dystrophy. Given their differences in phenotype, the most plausible explanation would be that these different retinal disorders are caused by mutations in different genes mapping close together within the genome.

Further studies on the identification of the phagocytosis receptor of rat retinal pigment epithelial cells.

We have previously produced a polyclonal antiserum (R1S5) against a plasma membrane-enriched fraction of rat retinal pigment epithelial (RPE) cells which inhibits the phagocytosis of photoreceptor outer segments (OS) by these cells. This antiserum has now been used to purify a subset of RPE membrane glycoproteins. Using a combination of lectin affinity chromatography, and chromatography on an affinity column made with R1S5-IgG, we have enriched an RPE membrane extract about 100-fold. This enriched extract contains only 12 components, all of which are glycoproteins, and retains the ability to adsorb out the inhibitory activity of antiserum R1S5. This shows that one or more of these glycoproteins recognizes an inhibitory IgG in R1S5 and suggests that one or more of these glycoproteins may participate in the phagocytosis of OS by RPE cells, possibly as the phagocytosis receptor. We have performed N-terminal microsequencing of seven of these glycoproteins: four of the seven, with Mrs of 34, 36, 51 and 55 kDa, show no sequence homology to any known proteins.

The gene responsible for autosomal dominant Doyne's honeycomb retinal dystrophy (DHRD) maps to chromosome 2p16.

Degeneration in the macula region of the retina is a feature of a heterogeneous group of inherited, progressive disorders, causing blinding visual impairment. Autosomal dominant Doyne's honeycomb retinal dystrophy (DHRD) is characterised by the presence of drusen deposits at the level of Bruch's membrane in the macula and around the edge of the optic nerve head. We have studied 63 members of a large, nine-generation British pedigree by linkage analysis. Two-point analysis showed significant linkage to nine markers on the short arm of chromosome 2, a region overlapping that recently reported to be linked to Malattia leventinese. A maximum lod score (Zmax) of 7.29 (theta = 0.0) was obtained at marker locus D2S2251. Haplotype analysis of recombination events localised the disease to a 5 cM region between marker loci D2S2316 and D2S378. Striking clinical similarities between DHRD and the more common condition age-related macular degeneration (ARMD) suggest that the disease gene at this locus could be considered as the most likely candidate in future studies on ARMD.

Sorsby's fundus dystrophy in the British Isles: demonstration of a striking founder effect by microsatellite-generated haplotypes.

Sorsby's fundus dystrophy (SFD) has been mapped to a genetic interval of 8 cM between loci D22S275 and D22S278. A total of 15 families, unrelated on the basis of genealogy and expressing the SFD phenotype were identified from a large data base of genetic eye disease families originating from diverse parts of the British Isles. The identification of the same Ser181Cys mutation cosegregating with disease in each family led us to consider the hypothesis of a founder effect being present. In all families studied, the same relatively infrequent allele (occurring in just 11% of the control group) was associated with disease at marker locus D22S280. A highly significant disease-associated haplotype, spanning across 3 cM of the SFD locus, was conserved in 11 of the 15 families (68% of all affected chromosomes); a further extended haplotype spanning up to 7 cM, was identified in 5 families (27% of SFD-associated chromosomes) and possibly represents the ancestral haplotype. This haplotype analysis has refined the TIMP3 gene localization to a 1- to 3-cM interval between marker loci D22S273 and D22S281 and provides strong evidence for a single mutational event being responsible for the majority of SFD identified in the British Isles.

Doyne revisited.

Inherited retinal dystrophies are important causes of blindness in the Western world. Molecular genetic techniques, and the use of large pedigrees exhibiting such conditions, have been instrumental in finding causative disease genes. The genealogy of families with a rare condition known as Doyne's honeycomb retinal degeneration was first described in 1899. Investigating this phenotype is extremely important because of the similarities it shares with age-related macular degeneration, and it may lead us to a gene that is involved in this complex genetic trait. In this paper we review the original genealogy of the families described by Doyne, and explain the methods used to identify the living descendants of these families.

Localization of the gene for progressive bifocal chorioretinal atrophy (PBCRA) to chromosome 6q.

Progressive bifocal chorioretinal atrophy (PBCRA) is a rare, autosomal dominant congenital chorioretinal dystrophy. We have performed genetic linkage analysis on a five-generation British pedigree. Two-point linkage analysis showed significant linkage with nine microsatellite marker loci mapping to chromosome 6q. Multipoint analysis gave a maximum lod score of 11.8 (theta = 0.05) between D6S249 and D6S283. This region overlaps with that to which the gene for North Carolina macular dystrophy (MCDR1) has been assigned. However, given the range of differences in phenotype between these two retinal disorders, it is likely that different mutation mechanisms are responsible for each disease.

Genetic refinement of the chromosome 5q lattice corneal dystrophy type I locus to within a 2 cM interval.

Lattice corneal dystrophy type I (LCDI) is a relatively common corneal dystrophy which can cause severe visual impairment. Recent studies have suggested a genetic localisation for the disease to chromosome 5q. Independent genetic linkage analysis in a six generation LCDI pedigree confirmed linkage to the 5q region bounded by marker loci IL9 and D5S436 suggesting genetic homogeneity. A maximum two point lod score of 7.51 (theta = 0.03) was obtained with marker D5S393. Multipoint and haplotype data positioned the disease between loci D5S393 and D5S396 corresponding to a genetic distance of 2cM, thus refining linkage sufficiently to allow for physical mapping of this disorder.

Linkage refinement localises Sorsby fundus dystrophy between markers D22S275 and D22S278.

Sorsby fundus dystrophy is an autosomal dominant disorder which both clinically and histopathologically bears striking similarities to age related macular degeneration, one of the leading causes of blindness in the developed world. Recent studies have suggested a genetic localisation of the disease to chromosome 22q in a large genetic interval of approximately 25 cM. Independent genetic linkage analysis in a six generation British pedigree confirms linkage to the chromosome 22q region. A maximum two point lod score of 7.09 with no recombination was obtained with marker D22S280. Haplotype data positioned the disease between loci D22S275 and D22S278, thus significantly reducing the region on chromosome 22q where the gene is located.

Autosomal dominant macular dystrophy simulating North Carolina macular dystrophy.

OBJECTIVE: To characterize an autosomal dominant macular dystrophy with highly variable expression that does not fall clearly into a known disease entity. METHODS AND PATIENTS: Clinical, angiographic, and electrophysiologic data of five affected members in a family of Indian origin were evaluated. Molecular genetic analysis was undertaken to assess whether the gene responsible for the phenotype in this pedigree mapped to a region previously assigned to dominantly inherited macular dystrophies, including North Carolina macular dystrophy. RESULTS: The fundus appearance in the proband simulated stage 3 North Carolina macular dystrophy. Affected relatives had features in common with pattern dystrophy, fundus flavimaculatus with a dark choroid, and dominantly inherited drusen. Linkage to loci assigned to a number of retinal dystrophies principally affecting the posterior pole, including the North Carolina macular dystrophy locus, was excluded. CONCLUSION: The findings support the view that different genotypes are associated with similar phenotypes in autosomal dominant macular dystrophy.

The role of molecular genetics in the prenatal diagnosis of retinal dystrophies.

Inherited retinal dystrophies are important causes of incurable blindness in developed countries. Advances in molecular genetics promise significant improvements in their management. Immediate benefits of present knowledge are presymptomatic and prenatal diagnosis in selected cases. To study the predictive power of these techniques a simulated genetic risk estimation was undertaken in a cone-rod retinal dystrophy pedigree known to be linked to chromosome 19. Using data on five fully informative, flanking DNA markers, phenotype was correctly assigned with only a 2% probability of error. If the two most closely linked markers were found to be uninformative, this error probability remained unchanged. Using genetic risk calculations and direct mutation detection many retinal dystrophies could now be identified by prenatal diagnosis.

Further refinement of the location for autosomal dominant retinitis pigmentosa on chromosome 7p (RP9).

A form of autosomal dominant retinitis pigmentosa (adRP) mapping to chromosome 7p was recently reported by this laboratory, in a single large family from southeastern England. Further sampling of the family and the use a number of genetic markers from 7p have facilitated the construction of a series of multipoint linkage maps of the region with the most likely disease gene location. From this and haplotype data, the locus can now be placed between the markers D7S484 and D7S526, in an interval estimated to be 1.6-4 cM. Genetic distances between the markers previously reported to be linked to this region and those described in the recent whole-genome poly-CA map were estimated from data in this and other families. These data should assist in the construction of a physical map of the region and will help to identify candidate genes for the 7p adRP locus.

Stimulation of A2 adenosine receptors inhibits the ingestion of photoreceptor outer segments by retinal pigment epithelium.

PURPOSE: Recent studies have shown that A2 adenosine receptors are present in retinal pigment epithelium (RPE). In this study, the effect of adenosine and adenosine analogues on photoreceptor outer segment (ROS) phagocytosis by RPE was investigated. METHODS: Primary cultures of RPE cells were incubated with isolated outer segments in the presence of various adenosine derivatives. Changes in adenylyl cyclase activity was measured by cyclic adenosine monophosphate (cAMP) production using a radioimmunoassay detection system. RESULTS: Adenosine inhibited the ingestion phase of phagocytosis (IC50 = 50 microM), and this effect was potentiated 80-fold in the presence of dipyridamole (IC50 = 0.6 microM). In the presence of 10 microM 8-phenyltheophylline, the inhibitory effect of 100 microM adenosine was reduced from 80% inhibition of ROS ingestion to 33% inhibition. The rank order of potency of adenosine analogues to inhibit ROS ingestion by RPE was N6-cyclohexyladenosine/5'-[N-ethylcarboxamido]-adenosine (NECA) = NECA > adenosine >> [R]-N6-[2-phenylisopropyl]-adenosine. The greatest stimulation of cAMP production was observed with 33.3 microM NECA: The production of cAMP reached its maximum level after 2 minutes of incubation, and after 10 minutes the levels of cAMP were back to basal. CONCLUSIONS: These results suggest that adenosine and adenosine analogues modulate ROS ingestion by RPE via activation of adenosine A2b receptors, possibly through the cAMP intracellular signaling pathway.

Genetic linkage of cone-rod retinal dystrophy to chromosome 19q and evidence for segregation distortion.

Inherited retinal dystrophies are the most common cause of childhood blindness in the developed world. Cone-rod retinal dystrophies are severe examples of this group of disorders. Analysis of a large cone-rod dystrophy pedigree suggested that inheritance within the family was influenced by meiotic drive (p = 0.008), a rare segregation distortion in human genetics. Two-point linkage analysis showed significant linkage with three markers mapping to chromosome 19q. Multipoint analysis gave a maximum lod score of 10.08 (theta = 0.05) distal to D19S47. Cone-rod dystrophy is therefore assigned to 19q13.1-q13.2 and a new candidate locus for other retinal dystrophies is identified.

Progressive retinal atrophy: a model for retinitis pigmentosa in companion animals.

The generalised progressive atrophies (PRA's) are a heterogeneous group of inherited retinopathies in dogs and cats. They show marked similarities to the retinitis pigmentosas (RP) in man, as well as to a number of inherited retinal degenerations of laboratory rodents. Of the various recessively inherited forms of PRA in the dog, that in the Irish setter is due to a nonsense mutation in the gene encoding cGMP-PDE-beta subunit. Mutations at this locus are also known to cause a proportion of human RP cases. We are interested in applying gene therapy to these diseases.